Action Points

Pairing rivaroxaban (Xarelto) with a P2Y12 inhibitor in the post-acute coronary syndromes (ACS) setting led to a similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor.

Note that there also was no difference in ischemic event outcomes between treatment with aspirin or rivaroxaban, although the trial was underpowered to find those differences. This was phase II trial so it should not change practice.

WASHINGTON -- Pairing rivaroxaban (Xarelto) with a P2Y12 inhibitor in the post-acute coronary syndromes (ACS) setting led to a similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor, researchers reported here.

In the GEMINI-ACS trial, the risk of clinically significant bleeding events occurred among 5% of patients treated with rivaroxaban and in 5% of patients treated with aspirin in addition to treatment with either clopidogrel (Plavix) or ticagrelor (Brilinta) for a hazard ratio of 1.09 (95% CI 0.80-1.50, P=0.5840), according to E. Magnus Ohman, MBBS, of the Duke Clinical Research Institute (DCRI) at Duke University in Durham, N.C., and colleagues.

There also was no difference in ischemic event outcomes between treatment with aspirin or rivaroxaban, although the trial was underpowered to find those differences, Ohman said in a presentation at the American College of Cardiology (ACC) annual meeting. The trial results were simultaneously published in the The Lancet.

"This was a phase II trial so it shouldn't change practice. This was a stepping stone to try to understand these regimens," Ohman told MedPage Today.

But he added that "this study is important because it is the first to show that replacing aspirin with a newer, more targeted drug -- low-dose rivaroxaban, an anticoagulant -- presents no additional risk of bleeding complications when given as dual therapy with an anti-platelet drug."

The current standard of care for ACS is for patients to take life-long aspirin, even though there is little evidence that this is an effective way to prevent a recurrent heart attack after early-phase ACS, Ohman explained.

Current guidelines from the ACC and the American Heart Association recommend treatment with dual anti-platelet therapy (DAPT) for ACS. A previous study showed that nearly 10% of patients treated with DAPT will still suffer major cardiovascular events during follow-up, Ohman's group noted.

Study Details

GEMINI-ACS enrolled 3,037 patients, with an average age of 63, from April 22, 2015 to Oct. 14, 2016. The majority of participants were white men who were enrolled within 10 days of being hospitalized for unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers, They also had either ischemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography.

Patients were excluded if they had a history of impaired kidney function, active bleeding, or bleeding in the brain or gastrointestinal tract within the previous year.

After patients had been on a stable dose of clopidogrel or ticagrelor for more than 48 hours, they were randomly assigned to receive either rivaroxaban at a low dose of 2.5 mg twice a day or aspirin at a dose of 100 mg a day in addition to clopidogrel or ticagrelor." The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference," the authors pointed out.

Patients were treated for a median of 291 days; the median follow-up period was 326 days. The number of patients who discontinued the study treatment prematurely was similar in both the rivaroxaban and aspirin groups -- 11.3% of those treated with rivaroxaban and 12.7% of patients treated with aspirin.

For the main bleeding endpoint, Ohman reported that 74 of 1,518 patients on aspirin and 80 of 1,519 patients assigned to rivaroxaban experienced clinically significant non-coronary artery bypass graft-related bleeding as defined by the Thrombosis in Myocardial Infarction (TIMI) investigators. Two fatal bleeds occurred in the rivaroxaban group of patients; none of the aspirin patients experienced a fatal bleed in the study.

During the study, 1% of patients in each group experienced a fatal MI, while 3% of patients taking aspirin and 4% taking rivaroxaban patients experienced MIs. Ohman reported that 1.5% of patients in the aspirin arm and 1% of patients in the rivaroxaban arm died during the trial. None of the differences achieved statistical significance.

The study had limitations, namely that patients had to be on stable therapy with either clopidogrel or ticagrelor with aspirin for 48 hours before they could be randomly assigned to either aspirin or rivaroxaban. This led to a delay of about 5 days from the index event to randomization, the authors noted. In addition, the study population was relatively homogeneous.

Not Ready for Prime-Time

"This study will not change clinical practice," commented Keith Fox, MD, of the University of Edinburgh, who was not involved in the trial. "It is important to remember that this a phase II trial. What it shows is that rivaroxaban is not inferior, within the limitations of this trial, against what may be regarded as the reference standard, which is aspirin. To change practice we would need to see evidence of efficacy or safety.

But as a safety trial, the results "showed that low-dose rivaroxaban is as safe as aspirin in these patients," noted Patrick O'Gara, MD, of Brigham & Women's Hospital in Boston. "But this study doesn't tell us if it is as effective, less effective, or more effective in preventing events."

O'Gara, who was not involved in the study, told MedPage Today that if he had a patient who was unable to take aspirin, he might consider an anticoagulant in the setting of ACS along with another anti-platelet agent. "But these patients are relatively rare," he said.

In an accompanying commentary, Paul A. Gurbel, MD, and Udaya S. Tantry, PhD, both of the Inova Heart and Vascular Institute in Falls Church, Va., pointed out that "almost all bleeding metrics were non-significantly lower with aspirin and a 50% increased bleed rate with rivaroxaban cannot be excluded. The primary endpoint was non-significantly higher with ticagrelor versus clopidogrel, irrespective of aspirin or rivaroxaban therapy."

They suggested that it may be "premature" to switch to rivaroxaban on top of a P2Y12 inhibitor in stabilized ACS patients.

"The totality of the evidence of GEMINI-ACS-1 favors aspirin ... a clearer mechanistic understanding of how so-called thrombin pathway inhibition compares with TxA2-dependent pathway inhibition on top of P2Y12 inhibition seems necessary before undertaking larger attempts to replace the cornerstone," they wrote.

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